Bottom Line:
The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress.Apoptosis contributes to neuronal death in many neurological disorders, including AD.In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

Affiliation: Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.

ABSTRACTOxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Both AD and arguably its earlier form, mild cognitive impairment (MCI), have elevated membrane oxidative damage in brain. The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. Apoptosis contributes to neuronal death in many neurological disorders, including AD. In this study, we investigated p53 expression in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD brain, to test the hypothesis that alterations of this pro-apoptotic protein may be involved in neuronal death in the progression of AD. By immunoprecipitation assay, we also investigated whether 4-hydroxy-2-transnonenal (HNE), an aldehydic product of lipid peroxidation, was bound in excess to p53 in IPL from subjects with MCI and AD compared to control. Overall, the data provide evidence that p53 is involved in the neuronal death in both MCI and AD, suggesting that the observed alterations are early events in the progression of AD. In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

fig01: (A) and (B) represent blots of the levels of p53 in the IPL from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amounts of protein (75 mg/lane) were electrophoresed using SDS-PAGE. Proteins were transferred to nitrocellulose membranes and probed with the primary anti-p53 antibody. (A) is a representative blot of data obtained from seven control and MCI samples, and (B) is a representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared.*P < 0.04;AD, #P < 0.015.

Mentions:
The IPL region exhibits severe histopathologic alterations in AD, that correlate to oxidative damage [37], including elevated lipid peroxidation [25, 38]. To determine whether p53 levels were elevated in MCI (Fig. 1A) and AD (Fig. 1B), the results of Western blotting of IPL were compared to control. Statistical analysis of p53 expression data found a significant increase of p53 levels in both MCI (*P < 0.04) and AD (#P < 0.015), compared to controls. These results are consistent with the notion that neurons are degenerating in this particular region of the cerebral cortex by p53-dependent pathways from an early stage of AD. p53 levels are largely regulated in response to injury by changes in protein degradation, although this may not necessarily apply to post-mitotic cells such as neurons. In fact, most studies of p53 were performed on non-neuronal cells, but some laboratory investigated the role of p53 in neuronal cell death. They found in the primary culture of rat cerebellar granule cells an increase of p53-immunoreactivity and p53 DNA binding activity after exposure to excitatory conditions [39]. These data in total suggest that neuronal cells are very sensitive to apoptosis, and different triggers, such involved also in neurodegenerative conditions as excitotoxicity, increasing of intracellular calcium concentration, oxygen free radical production, could activate the apoptotic pathway by p53.

fig01: (A) and (B) represent blots of the levels of p53 in the IPL from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amounts of protein (75 mg/lane) were electrophoresed using SDS-PAGE. Proteins were transferred to nitrocellulose membranes and probed with the primary anti-p53 antibody. (A) is a representative blot of data obtained from seven control and MCI samples, and (B) is a representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared.*P < 0.04;AD, #P < 0.015.

Mentions:
The IPL region exhibits severe histopathologic alterations in AD, that correlate to oxidative damage [37], including elevated lipid peroxidation [25, 38]. To determine whether p53 levels were elevated in MCI (Fig. 1A) and AD (Fig. 1B), the results of Western blotting of IPL were compared to control. Statistical analysis of p53 expression data found a significant increase of p53 levels in both MCI (*P < 0.04) and AD (#P < 0.015), compared to controls. These results are consistent with the notion that neurons are degenerating in this particular region of the cerebral cortex by p53-dependent pathways from an early stage of AD. p53 levels are largely regulated in response to injury by changes in protein degradation, although this may not necessarily apply to post-mitotic cells such as neurons. In fact, most studies of p53 were performed on non-neuronal cells, but some laboratory investigated the role of p53 in neuronal cell death. They found in the primary culture of rat cerebellar granule cells an increase of p53-immunoreactivity and p53 DNA binding activity after exposure to excitatory conditions [39]. These data in total suggest that neuronal cells are very sensitive to apoptosis, and different triggers, such involved also in neurodegenerative conditions as excitotoxicity, increasing of intracellular calcium concentration, oxygen free radical production, could activate the apoptotic pathway by p53.

Bottom Line:
The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress.Apoptosis contributes to neuronal death in many neurological disorders, including AD.In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

Affiliation:
Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.

ABSTRACTOxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Both AD and arguably its earlier form, mild cognitive impairment (MCI), have elevated membrane oxidative damage in brain. The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. Apoptosis contributes to neuronal death in many neurological disorders, including AD. In this study, we investigated p53 expression in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD brain, to test the hypothesis that alterations of this pro-apoptotic protein may be involved in neuronal death in the progression of AD. By immunoprecipitation assay, we also investigated whether 4-hydroxy-2-transnonenal (HNE), an aldehydic product of lipid peroxidation, was bound in excess to p53 in IPL from subjects with MCI and AD compared to control. Overall, the data provide evidence that p53 is involved in the neuronal death in both MCI and AD, suggesting that the observed alterations are early events in the progression of AD. In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.